Dual-pathway targeted therapy for Parkinson's disease: Biomimetic nanosomes inhibit ferroptosis and pyroptosis through NLRP3 inflammasome regulation

Parkinson's disease (PD), a progressive neurodegenerative disorder, is marked by the degeneration of dopaminergic neurons. Emerging evidence highlights the critical involvement of neuronal ferroptosis and microglial pyroptosis in PD pathogenesis. In this study, we first characterized systemic inflammatory alterations in the peripheral blood of PD patients compared to healthy controls, revealing distinct pro-inflammatory signatures. Based on these findings, we engineered BV2 microglial membrane-camouflaged biomimetic multienzyme gallic acid-selenium nanoparticles (BM@GA-Se nanosomes) and evaluated their neuroprotective potential. In vitro and in vivo experiments demonstrated that BM@GA-Se nanosomes enhanced neuronal survival by simultaneously suppressing ferroptosis of neurons (via GPX4-mediated lipid peroxide reduction) and pyroptosis of microglia (through inhibition of the HSP90/NLRP3/Caspase-1 signaling pathway). These results position BM@GA-Se nanosome as a new dual-pathway targeting therapeutic strategy, offering a promising translational approach to mitigate PD progression by addressing interdependent inflammatory and oxidative mechanisms. The highlights are. (1) Development of BM@GA-Se nanosomes, engineered using BV2 microglial membrane camouflage to enhance biocompatibility and targeting, combining biomimetic multienzyme gallic acid-selenium nanoparticles for dual antioxidant and anti-inflammatory effects. (2) The nanosomes were demonstrated a triple-pronged approach to neuroprotection: mitigating ferroptosis via RONS elimination and inhibiting pyroptosis by targeting the HSP90/NLRP3/Caspase-1 axis. (3) BM@GA-Se nanosomes showed significant improvement in motor function in a mouse model of Parkinson's disease, confirming their therapeutic potential.